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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to 7-alkynyl-1,8-naphthyridone derivatives, to their preparation and to their therapeutic application.
• . is a C 1 -C 7 alkyl group, a -CO-C 1 -C 7 alkyl group or a C 3 -C 8 cycloalkyl group, wherein said alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from halogen atoms and hydroxy and alkoxy groups,
• . is a phenyl group optionally substituted with one or more groups chosen from halogen atoms, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -halogenoalkoxy, -halogenoalkyl, -CN, -NRR 'groups, where R and R 'are as defined below,
• a heteroaryl group optionally substituted at any position, including a nitrogen atom of said heteroaryl, with one or more groups selected from halogen atoms, C1-C4 alkyl groups and -NRR 'groups where R and R 'are as defined below, (2) or R 1 and R 2 together with the carbon atom that carries them:
• . is a C4-C8 cycloalkyl group
• a 4- to 8-membered saturated heterocyclic group comprising a heteroatom selected from N, O and S 1 and said heterocyclic group fusible to a phenyl group;
• R 3 represents:
• . is a linear or branched C1-C7 alkyl group or a C3-alkyl group
• alkyl group being optionally substituted by one or more groups selected from halogen atoms and hydroxy, alkoxy, -NRR ", -haloalkyl and -SO 2 - (Cl- C4) alkyl, where R and R 'are as defined below;
• n O 1 1, 2 or 3 and wherein the heterocyclic group comprises between 4 and 8 members and comprises at least one heteroatom selected from N, O and S, where said heterocyclic group is optionally substituted by an oxo group,
• heteroaryl group comprises 5 or 6 members and comprises one or more heteroatoms selected from nitrogen, oxygen and sulfur ;
• R ⁇ represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group
• R and R ' represent independently of each other a hydrogen atom, a C1-C4 alkyl group.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixture, including their racemic mixture, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or salified by acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids or bases, but the salts of other acids or bases which are useful, for example, for the purification or the isolation of the compounds of formula (I), are also part of invention.
• the compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
• an alkyl group a saturated aliphatic group comprising from 1 to 7 carbon atoms (advantageously from 1 to 4 carbon atoms) and being linear or, when the alkyl chain comprises at least 3 carbon atoms, which can be linear, branched or partially cyclized.
• alkyl group a saturated aliphatic group comprising from 1 to 7 carbon atoms (advantageously from 1 to 4 carbon atoms) and being linear or, when the alkyl chain comprises at least 3 carbon atoms, which can be linear, branched or partially cyclized.
• a cycloalkyl group a cyclic alkyl group comprising from 3 to 8 carbon atoms and of which all the carbon atoms are engaged in the cycle. There may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups;
• alkoxy group a group -O-alkyl, where the alkyl group is as defined above;
• halogen atom a fluorine, a chlorine, a bromine or an iodine
• a haloalkyl group an alkyl group in which one or more hydrogen atoms have been substituted with a halogen atom; by way of example, mention may be made of -CF 3 ;
• haloalkoxy group an alkoxy group in which one or more hydrogen atoms have been substituted with a halogen atom; by way of example, mention may be made of -OCF 3 ; an aryl group: a monocyclic aromatic group, such as a phenyl group;
• heteroaryl group an aromatic group comprising 5 or 6 members and comprising one or more heteroatoms chosen from nitrogen, oxygen and sulfur.
• a heteroaryl group an aromatic group comprising 5 or 6 members and comprising one or more heteroatoms chosen from nitrogen, oxygen and sulfur.
• a heterocyclic group a cyclic alkyl group comprising between 4 and 8 ring members and comprising one or more heteroatoms chosen from nitrogen, oxygen and sulfur.
• a heterocyclic group a cyclic alkyl group comprising between 4 and 8 ring members and comprising one or more heteroatoms chosen from nitrogen, oxygen and sulfur.
• piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothienyl groups may be mentioned, for example, piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothienyl groups.
• . is a C 1 -C 7 alkyl group, a -CO-C 1 -C 7 alkyl group or a C 3 -C 8 cycloalkyl group, wherein said alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from halogen atoms and hydroxy and alkoxy groups,
• . is a phenyl group optionally substituted with one or more groups chosen from halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -OCF 3 , -CF 3 , -CN, -NRR 'groups, where R and R 'are as defined below,
• a heteroaryl group optionally substituted at any position, including a nitrogen atom of said heteroaryl, with one or more groups selected from halogen atoms, C1-C4 alkyl groups and -NRR 'groups where R and R 'are as defined below,
• R 1 and R 2 together with the carbon atom that carries them: . is a C4-C8 cycloalkyl group;
• a 4- to 8-membered saturated heterocyclic group comprising a heteroatom selected from N, O and S atoms, and said heterocyclic group fusible to a phenyl group;
• R 3 represents:
• . is a linear or branched C1-C7 alkyl group or a C3-alkyl group
• alkyl group being optionally substituted with one or more groups selected from halogen atoms and hydroxy, alkoxy, -NRR ', -CF 3 and -SO 2 - (CI -C4) alkyl, where R and R 'are as defined below;
• heterocyclic group comprises between 4 and 8 members and comprises at least one heteroatom selected from N, O and S, where said heterocyclic group is optionally substituted by an oxo group,
• R ⁇ represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group
• R and R ' represent independently of each other a hydrogen atom, a C1-C4 alkyl group.
• . is a C 1 -C 7 alkyl group, a -CO-C 1 -C 7 alkyl group or a C 3 -C 8 cycloalkyl group, wherein said alkyl group is optionally substituted by one or more groups selected from hydroxy and alkoxy groups,
• . is a phenyl group optionally substituted with one or more C1-C4 alkoxy groups
• . is a C4-C8 cycloalkyl group
• a 4- to 8-membered saturated heterocyclic group comprising a heteroatom selected from N, O and S atoms, and said heterocyclic group fusible to a phenyl group;
• Ra represents:
• . is a linear or branched C1-C7 alkyl group or a C3-alkyl group
• alkyl group being optionally substituted by one or more groups selected from hydroxy, alkoxy, -NRR ', haloalkyl and -SO 2 - (C 1 -C 4) alkyl, where R and R 'are as defined below;
• R ⁇ represents a C1-C4 alkyl group or a C1-C4 alkoxy group
• R and R 'each represents a linear or branched C1-C4 alkyl group.
• . is a C 1 -C 7 alkyl group, a -CO-C 1 -C 7 alkyl group or a C 3 -C 8 cycloalkyl group, wherein said alkyl group is optionally substituted by one or more groups selected from hydroxy and alkoxy groups,
• . is a C4-C8 cycloalkyl group; . a 4- to 8-membered saturated heterocyclic group comprising an oxygen heteroatom, and said heterocyclic group fusible to a phenyl group;
• R 3 represents:
• . is a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group of which at least 3 carbon atoms are cyclized, said alkyl group being optionally substituted with one or more groups chosen from hydroxyl, alkoxy, -NRR groups; ', haloalkyl and -SO 2 - (Cl -C 4) alkyl, wherein R and R 1 are as defined below;
• heterocyclic group comprises between 4 and 8 members and comprises at least one heteroatom selected from N, O, where said group heterocyclic is optionally substituted by an oxo group,
• R ⁇ represents a C1-C4 alkyl group or a C1-C4 alkoxy group
• R and R 'each represents a linear or branched C1-C4 alkyl group.
• . is a C 1 -C 7 alkyl group, or a C 3 -C 8 cycloalkyl group, wherein said alkyl group is optionally substituted with one or more groups selected from hydroxy and alkoxy groups,
• R ⁇ represents:
• . is a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group of which at least 3 carbon atoms are cyclized, said alkyl group being optionally substituted with one or more groups selected from hydroxy, alkoxy, haloalkyl and -SO 2 - (C 1 -C 4) alkyl;
• R ⁇ represents a C1-C4 alkyl group
• R 1 and R 'each represent a linear or branched C 1 -C 4 alkyl group.
• . is a C 1 -C 7 alkyl group, a -CO-C 1 -C 7 alkyl group or a C 3 -C 8 cycloalkyl group, wherein said alkyl group is optionally substituted by one or more groups selected from hydroxy and alkoxy groups,
• . is a phenyl group optionally substituted with one or more C1-C4 alkoxy groups
• . is a C4-C8 cycloalkyl group
• a 4- to 8-membered saturated heterocyclic group comprising a heteroatom selected from N, O and S atoms, and said heterocyclic group fusible to a phenyl group;
• . is a linear or branched C1-C7 alkyl group or a C3-alkyl group
• alkyl group being optionally substituted by one or more groups selected from hydroxy, alkoxy, -NRR ', haloalkyl and -SO 2 - (C 1 -C 4) alkyl, where R and R 'are as defined below;
• n 0, 1, 2 or 3 and wherein the heterocyclic group comprises between 4 and 8 members and comprises at least one heteroatom selected from N and O atoms, wherein said group heterocyclic is optionally substituted by an oxo group,
• n 0 or 1 and wherein the heteroaryl group comprises 5 or 6 members and comprises one or more nitrogen heteroatoms.
• R 3 represents a C 3 -C 7 alkyl group of which at least 3 carbon atoms are cyclized chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and methylene-cyclopropyl groups.
• a 2,6-dihalogenonicotinic acid of formula (II) in which the X groups represent halogen atoms (preferably chlorine or bromine), and which is either commercially available or is prepared according to the known methods of the person skilled in the art is monosubstituted at the 2-position by an amine of formula R 3 -NH 2 (where R 3 is as defined above in relation to the compounds of formula (I) which are subjects of the invention), at a temperature of between 20 ° C. and 150 ° C., in a protic solvent such as an alcohol or water and, optionally, in a sealed tube.
• a protic solvent such as an alcohol or water
• a 2-aminonicotinic derivative of formula (III) is obtained, which is converted into acid fluoride of formula (IV) by the action of cyanuryl fluoride at room temperature, in the presence of a base such as triethylamine or pyridine. and in an inert solvent such as dichloromethane, as described by G. OLAH et al. in Synthesis (1973), 487, or by other methods known to those skilled in the art, such as those described by MUKAIYAMA and TANAKA in Chem. Lett. (1976), 303 or by ISHIKAWA and SASAKI in Chem. Lett. (1976), 1407.
• a ⁇ -keto-cyanoacetamide of formula (VI) is obtained, which is then cyclized to amino-pyridino [2,3-b] pyridinone of formula (VII) either by heating at a temperature between 90 and 125 ° C in a polar solvent such as n-butanol, dimethylsulfoxide or dimethylformamide (method A) or by treating at room temperature with a strong base such that potassium tert-butoxide in an aprotic solvent, preferably tetrahydrofuran (method B).
• a polar solvent such as n-butanol, dimethylsulfoxide or dimethylformamide
• N-alkylcyanoacetamides of formula (V) are prepared by reacting cyanoacetic acid with an alkyl chloroformate (such as ethyl or isobutyl) in the presence of a base such as triethylamine, at a temperature of less than or equal to 0 0 C, then the mixed anhydride intermediate formed is reacted with an excess of amine of formula R 4 -NH 2 (where R 4 is as defined above in relation to the compounds of formula (I) which are the subject of the invention. invention).
• an alkyl chloroformate such as ethyl or isobutyl
• a base such as triethylamine
• the halogenated intermediate of formula (VII) is coupled according to the methods known to the man of the present invention. art with a suitable derivative of propargyl alcohol R 1 R 2 CH (OH) CCH of formula (VIII) wherein R 1 and R 2 are as defined for the compound of formula (I).
• the intermediate (VII) is engaged in a Sonogashira coupling reaction with the appropriate alkyne of formula (VIII) in the presence of PdCl 2 (PPh 3 ) 2 , triethylamine copper iodide and dimethylformamide, at a temperature between 80 ° C. and 120 ° C. This reaction can be carried out in a sealed tube and in a microwave.
• the hydroxyl group or certain reactive functions located on the groups R 1 , R 2 and R 3 may be temporarily protected by protecting groups known to those skilled in the art and as described in "Protective Groups in Organic Synthesis", Green et al., 2 nd Edition (John Wiley & Sons, Inc., New York).
• the starting compounds and the reagents when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or which are known to those skilled in the art.
• the invention also relates to the compounds of formula (VII) defined in FIG. 1. These compounds are useful as synthesis intermediates for the compounds of formula (I).
• the sealed tube is placed in the microwave oven (EMC device, model
• the residue obtained is purified by chromatography on silica (solid deposition, elution with a cyclohexane: ethyl acetate gradient, 30:70 to 20:80). 2.49 g of the expected product are obtained in the form of a pale yellow solid.
• the product can be recrystallized from ethanol to give white crystals.
• the residue obtained is purified by chromatography on silica (solid deposition, gradient elution CH 2 Cl 2 / MeOH / NH 4 OHaq, 98/2 / 0.2 to 95/5 / 0.5). After trituration in ether, 0.425 g of expected product is obtained in the form of a yellow solid.
• a new purification is carried out by chromatography on a silica column (elution with a cyclohexane: ethyl acetate gradient, 20:80 to 0: 100) and finally 0.068 g of the expected product is obtained in the form of a yellow solid.
• the oily residue is purified by chromatography on a silica column, eluting with a cyclohexane: ethyl acetate gradient, 100: 0 to 80: 20 to obtain 1.9 g of ( ⁇ ) -2-cyclopropyl-1-methoxy-4. - (trimethylsilyl) but-3-yn-2-ol as an oil with a yield of 51%.
• Table 1 which follows illustrates the chemical structures and the physical properties of some compounds of formula (I) according to the invention.
• Table 1 which follows illustrates the chemical structures and the physical properties of some compounds of formula (I) according to the invention. In this table :
• the asterisk "*" indicates, in the case where R 1 and R 2 together form a ring (heterocycle or cycloalkyl), the carbon of attachment of said ring to the adjacent carbon of the acetylenic bond, - Me and Et respectively represent groups methyl and ethyl,
• the column PF indicates the melting point, at 0 C, of the compound
• Solvent A H 2 O + 0.1% HCO 2 H
• solvent B ACN + 0.1% HCO 2 H
• flow rate 1 mL / min
• Solvent A 2-propanol / TFA (1000/1); solvent B: heptane / 2-propanol (1000/30) Isocratic: 50% A + 50% B
• the compounds according to the invention have been the subject of pharmacological tests for determining their inhibitory effect on the enzyme VEGFR-3.
• VEGFR-3 tyrosine kinase activity by ELISA
• the enzymatic activity of VEGFR-3 is evaluated on an ELISA test by measuring the phosphorylation intensity of the poly Glu-Tyr substrate.
• the effect of the products is quantified by the concentration which decreases the total activity of the enzyme by 50% (IC50).
• IC50 determination the product is diluted in DMSO with a concentration range ranging from 3 to 1000 nM.
• 125 ⁇ l of the Glu-Tyr poly substrate (250 ⁇ g / ml in 1x PBS without Ca 2+, neither Mg 2+ nor sodium bicarbonate) are deposited in each well of an ELISA plate (for example a plate SIGMA Protein Tyrosine Kinase Assay Kit ELISA, Ref PTK-101).
• the plate is then covered with an adhesive and incubated overnight at 37 ° C.
• the wells are emptied by inversion, washed by adding 300 .mu.l of buffer solution (PBS + 0.05% Tween 20) and dried by further incubation of the plate for 2 h at 37.degree. A reaction mixture of 90 .mu.l is deposited on each well.
• This mixture contains the 1X kinase buffer supplemented with 30 ⁇ M ATP and the inhibitor at the desired concentration. Then, 20 ⁇ l of VEGFR-3-TK (CeII signaling, Ref 7790), previously diluted in the kinase buffer without ATP, will be added (with the exception of negative control wells where 20 ⁇ l of buffer without enzyme will be added). The plates are then incubated with gentle shaking at room temperature for 30 min. After 3 rinses with the buffer solution (300 ⁇ l / well per wash), 100 ⁇ l of anti-Phospho tyrosine-HRP antibody (1 / 30,000). To each well is added and again the plates are incubated for 30 min at room temperature with gentle shaking.
• VEGFR-3-TK CeII signaling, Ref 7790
• the phosphorylation of the substrate is revealed by the addition of 100 ⁇ l per well of OPD substrate, 1 OPD pellet and 1 urea pellet in 20 ml of water (extemporaneous preparation and protected from light). After incubation for 7 minutes at room temperature and in the dark, the reaction is stopped by adding 100 ⁇ l H 2 SO 4 to 1.25 M (2.5 N) per well and the absorbance is read at 492 nm. . The total activity is evaluated by the difference in optical density obtained on samples incubated in the presence (stimulated) and absence (non-stimulated) of VEGFR-3.
• the compounds in accordance with the invention have IC50 values of less than 10 ⁇ M, most of them less than 1 ⁇ M.
• IC50 values of less than 10 ⁇ M, most of them less than 1 ⁇ M.
• Table 2 the IC 50's of some compounds of Table 1 are shown in Table 2 below.
• the compounds according to the invention have an inhibitory activity of the enzyme VEGFR-3; they can therefore be used for the preparation of medicaments, in particular drugs which inhibit VEGFR-3.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or base, or a hydrate or a solvate as well as an enantiomer or a diastereoisomer including their mixture of the compound of formula (I).
• Another aspect of the invention comprises an association between at least one compound according to the invention and at least one chemotherapy agent.
• the compounds of the present invention can be used alone or in admixture with at least one chemotherapy agent that can be chosen from:
• Combinations of the compounds of the invention with the chemotherapy agents mentioned above and / or radiation are another object of the present invention.
• the chemotherapy agents mentioned above and / or the radiation can be administered simultaneously, separately or sequentially.
• the treatment will be adapted by the practitioner according to the patient to be treated.
• glioblastoma multiple myeloma, myelodysplastic syndromes, Kaposi's sarcomas, cutaneous angiosarcomas, solid tumors, lymphomas, melanomas, breast cancers, colorectal cancers, lung cancers including non-small cancers cells, pancreatic cancers, prostate cancers, renal cancers, head and neck cancers, liver cancer, ovarian cancers, respiratory and thoracic cancers, other tumors expressing VEGFR-3 or involving a angiogenesis or lymphangiogenesis,
• non-oncological proliferative diseases and pathological angiogenesis related to VEGFR-3 such as: arthrosis, restenosis, psoriasis, hemangioma, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, thrombotic microangiopathic syndromes, cirrhosis of the liver, atherosclerosis, rejections of organ transplant, diseases of the eye involving a process of angiogenesis or lymphangiogenesis such as diabetic retinopathy or macular degeneration,
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its any salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment or prevention of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

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